Prostaglandin D2 (abbreviated as PGD2) is known as a metabolite produced via an arachidonic acid cascade and is considered to be one of the chemical mediators involved in allergic diseases such as allergic rhinitis, bronchial asthma and allergic conjunctivitis. It is known that PGD2 is mainly produced in and released from mast cells and that the released PGD2 provides contraction of bronchus, promotion of vascular permeability, dilation or contraction of blood vessels, promotion of mucus secretion, inhibition of platelet aggregation, etc. It has been also reported that PGD2 induces bronchoconstriction and nasal obstruction in vivo and increased the production of PGD2 in pathological lesion of patients suffering from systemic mastocytosis, allergic rhinitis, bronchial asthma, atopic dermatitis, urticaria, etc. (N. Engl. J. Med. 1980; 303: 1400-4, Am. Rev. Respir. Dis. 1983; 128: 597-602, J. Allergy Clin. Immunol. 1991; 88: 33-42, Arch. Otolaryngol. Head Neck Surg. 1987; 113: 179-83, J. Allergy Clin. Immunol. 1988; 82: 869-77, J. Immunol. 1991; 146: 671-6, J. Allergy Clin. Immunol. 1989; 83: 905-12, N. Eng. J. Med. 1986; 315: 800-4, Am. Rev. Respir. Dis. 1990; 142, 126-32, J. Allergy Clin. Immunol. 1991; 87: 540-8, J. Allergy Clin. Immunol 1986; 78: 458-61). PGD2 has been also reported to be involved in neural activity, particularly in sleeping, hormone secretion, and pain. Furthermore, it has been also reported that it is involved in platelet aggregation, glycogen metabolism and adjustment of intraocular pressure, etc.
WO 2005/028455 (Patent Document 1, hereinafter) describes that a compound represented by formula (A) binds to a DP receptor and behaves as an antagonist:
wherein,R1A represents (1) a hydrogen atom, (2) C1-4 alkyl group, etc.,EA represents —CO group etc.,R2A represents (1) a halogen atom, (2) C1-6 alkyl group, (3) C1-6 alkoxy group, (4) hydroxyl group, (5) trihalomethyl group, (6) cyano group, (7) phenyl group, (8) pyridyl group, (9) nitro group, (10) —NR6AR7A group, (11) C1-4 alkyl group substituted with —OR8A group, (12) oxidized C1-6 alkyl group, (13) —SO2R11A group, (14) —SOR11A group, or (15) —SR11A group,R3A represents (1) a halogen atom or (2) C1-6 alkyl group, etc.,R6A and R7A each independently represents a hydrogen atom or C1-4 alkyl group,R8A represents C1-4 alkyl, phenyl, or pyridyl group,R4A represents (1) a hydrogen atom, etc.,R5A represents (1) C1-6 alkyl, or (2) C1-10 alkoxy, etc.,R11A represents C1-6 alkyl group, or optionally substituted phenyl group,ring WA represents a C5-12 monocyclic or bicyclic carbon ring, etc.,GA represents (1) C1-6 alkylene group etc. having 0-2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,ring JA represents a 5-12 membered monocyclic or bicyclic heterocyclic ring, etc.,mA represents 0 or an integer from 1 to 4,nA represents 0 or an integer from 1 to 4,iA represents 0 or an integer from 1 to 11,R12A and R13A each independently represents (1) optionally oxidized C1-4 alkyl group, (2) a halogen atom, (3) trihalomethyl group, (4) optionally protected hydroxyl group, (5) optionally protected amino group, (6) optionally substituted phenyl group, (7) optionally substituted pyridyl group, or (8) a hydrogen atom, or R12A and R13A taken together represent (1) oxo group, (2) C2-5 alkylene group in which a carbon atom is optionally replaced by an oxygen atom, nitrogen atom, or sulfur atom, wherein the C2-5 alkylene group is optionally substituted by a substituent, or (3) optionally substituted C1-6 alkylidene group.(The necessary parts of the explanation for the groups are selectively described.)(See Patent Document 1).
WO 03/078409 (Patent Document 2, hereinafter) describes that a compound represented by formula (B) binds to a DP receptor and behaves as an antagonist:
whereinR1B represents (1) a hydrogen atom or (2) C1-4 alkyl group, etc.,EB represents —C(═O)— group, etc.,R2B represents (1) a halogen atom, (2) C1-6 alkyl group, (3) C1-6 alkoxy group, (4) hydroxyl group, (5) trihalomethyl group, (6) cyano group, (7) phenyl group, (8) pyridyl group, (9) nitro group, (10) —NR6BR7B group, or (11) C1-4 alkyl group substituted by —OR8B group,R3B represents (1) a halogen atom or (2) C1-6 alkyl group, etc.,R6B and R7B each independently represents a hydrogen atom or C1-4 alkyl group,R8B represents C1-4 alkyl group, phenyl group, or pyridyl group,R4B represents (1) hydrogen atom, etc.,R5B represents (1) C1-6 alkyl group, or (2) C1-10 alkoxy group, etc.,ring WB represents C5-12 monocyclic or bicyclic carbon ring, etc.,GB represents (1) C1-6 alkylene group, etc. containing 0-2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,ring JB represents 5-12 membered monocyclic or bicyclic heterocyclic ring, etc.,mB represents 0 or an integer from 1 to 4,nB represents 0 or an integer from 1 to 4,iB represents 0 or an integer from 1 to 11.(The necessary parts of explanation for the groups are selectively described.)(See to Patent Document 2).
Although Patent Document 1 and 2 list the types of substituents represented by R2A and R2B, there is no description of the most preferable substitution position, and there is no description or suggestion of the effects due to the substituent type and the substitution position.
Further, there is no description in Patent Documents 1 and 2 that the drug-metabolizing enzyme is inhibited by introducing a specific substituent at a specific substitution position of the compound represented by formulae (A) and (B), and therefore naturally, no description or suggestion for the means to solve the problem is given therein.
Additionally, there is no description in Patent Documents 1 and 2 that, depending on the combination of the substituent type and the substitution position, the compounds represented by formulae (A) and (B) may have insufficient selectivity against other receptors and therefore naturally, no description or suggestion for the means to solve the problem is given therein.